2-47416422-G-T

Variant names:

• chr2-47416422-G-T
• rs587779069
• NM_000251.3:c.1069G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000251.3(MSH2):​c.1069G>T​(p.Glu357*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E357E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.81
• Publications: 0 publications found

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47416422-G-T is Pathogenic according to our data. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47416422-G-T is described in CliVar as Pathogenic. Clinvar id is 1782830.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1069G>T	p.Glu357*	stop_gained	Exon 6 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1069G>T	p.Glu357*	stop_gained	Exon 6 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

May 08, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E357* pathogenic mutation (also known as c.1069G>T), located in coding exon 6 of the MSH2 gene, results from a G to T substitution at nucleotide position 1069. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This variant has been reported in a French individual with Lynch syndrome (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.8
Vest4		0.96
GERP RS		5.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587779069; hg19: chr2-47643561;